Atropine Eye Drops: An Unusual Homicidal Poisoning

In March 2009, the body of a 51‐year‐old man was found in the boot of his car. The body had been frozen before being dismembered at the abdomen. The autopsy failed to determine the cause of death. Systematic toxicological analyses of the victim's peripheral blood and urine showed the presence of atropine, a powerful anticholinergic. Atropine was therefore specifically detected and quantified throughout the victim's biologic samples by HPLC‐MS² in the biologic fluids and UHPLC‐MS² in the hair. The atropine concentrations were 887 ng/mL in the cardiac blood, 489 ng/mL in the peripheral blood, 6693 ng/mL in the gastric contents (1.1 μg), 6753 ng/mL in the urine, and 2290 pg/mg in the hair. The blood concentrations measured in the decedent were consistent with an overdose of atropine, which was determined as the cause of death. The manner of death was a homicide with criminal intent.     

Phencyclidine: a 5-year retrospective review from the New York City Medical Examiner's Office

We report here a 5-year retrospective review of autopsy cases from the New York City Medical Examiner's Office that demonstrated phencyclidine (PCP) in the blood. There were a total of 138 cases. There were 52 deaths because of mixed drug intoxication: the blood PCP concentrations in these cases ranged from <1 to 598 ng/mL. There were 80 violent deaths in which PCP was quantified in the blood but was unrelated to the cause of death. There were five nonviolent deaths in which PCP exclusively was detected. In four of these, there were preexisting medical conditions that could also have contributed to death. In these, the highest PCP concentration was 361.3 ng/mL, a concentration lower than seven of the individuals in our violent death category. This suggests that lower concentrations may be fatal with comorbid conditions.     

Postmortem Liver and Kidney Tissue Concentrations of Heroin Biomarkers and Their Metabolites in Heroin-Related Fatalities*†

A method was developed and validated for analyzing 6-monoacetylmorphine, morphine, 6-acetylcodeine, and codeine in routine postmortem liver and kidney specimens using liquid chromatography–tandem mass spectrometry. Samples were prepared with a Stomacher instrument followed by solid-phase extraction. All calibration curves [0.5–1000 ng/g] were linear with coefficients of determination greater than 0.99 and limits of quantification of 1.0 ng/g. Within-run precision ranged between 2.0% and 8.0%, between-run precision ranged between 1.0% and 9.0%, and accuracy ranged between −5.0% and +3.0%. Matrix effects ranged from −18% to +9%. After matrix effects were excluded, analytical recoveries ranged from 76% to 94%. The distributions of 6-monoacetylmorphine, morphine, 6-acetylcodeine, and codeine were investigated in 31 postmortem cases in which heroin was the primary cause of death. In the current study, the median free morphine ratios were calculated for liver to blood and kidney to blood, which were 2.2 and 4.0, respectively. The current report highlights the importance of testing multiple specimens, including liver and kidney, in heroin-related deaths, especially if no blood samples are available. Furthermore, this work presents new information regarding the distribution of heroin metabolites in liver and kidney.     

A Fatal Case of Poisoning with Fentanyl Transdermal Patches in Japan

Fentanyl transdermal patches have been used to treat cancer‐ and noncancer‐related chronic pain. However, its inappropriate or illegal application may cause fatal poisoning. We herein present the case of a Japanese woman in her 40s who was found dead with seven 25‐μg/h fentanyl transdermal patches on her body. We established a detailed toxicological analysis procedure to quantify fentanyl, and its metabolite norfentanyl, and other drugs (acetaminophen, allylisopropylacetylurea, celecoxib, estazolam, promethazine, and sertraline) in human whole blood by ultra‐high‐performance liquid chromatography–tandem mass spectrometry. The measured fentanyl and norfentanyl concentrations in the femoral and cardiac blood were 0.051 and 0.072 μg/mL and 0.033 and 0.076 μg/mL, respectively. The decedent's fentanyl concentrations were consistent with previously reported postmortem blood levels for fatal cases of poisoning by fentanyl transdermal patches. Based on the decedent's case history, autopsy findings, and toxicological analyses, the cause of death was identified as intoxication with transdermal fentanyl.     

Deaths Involving Methylenedioxypyrovalerone (MDPV) in Upper East Tennessee

Two deaths involving 3, 4‐methylenedioxypyrovalerone (MDPV) are reported. MDPV is a synthetic cathinone stimulant found in “bath salts” with neurological and cardiovascular toxicity. Biological specimens were analyzed for MDPV by GC/MS and LC/MS. A White man was found dead with signs of nausea and vomiting after repeatedly abusing bath salts during a weekend binge. Femoral venous blood and urine had MDPV concentrations of 39 ng/mL and 760 ng/mL. The second fatality was a White man with a history of drug and bath salt abuse found dead at a scene in total disarray after exhibiting fits of anger and psychotic behavior. Femoral venous blood and urine had MDPV concentrations of 130 ng/mL and 3800 ng/mL. The blood and urine MDPV concentrations are within the reported recreational concentration ranges (blood 24–241 ng/mL and urine 34–3900 ng/mL). Both decedents’ deaths were attributed to relevant natural causes in a setting of MDPV abuse.     

Report of Increasing Overdose Deaths that include Acetyl Fentanyl in Multiple Counties of the Southwestern Region of the Commonwealth of Pennsylvania in 2015–2016

Acetyl fentanyl is a Schedule I controlled synthetic opioid that is becoming an increasingly detected “designer drug.” Routine drug screening procedures in local forensic toxicology laboratories identified a total of 41 overdose deaths associated with acetyl fentanyl within multiple counties of the southwestern region of the state of Pennsylvania. The range, median, mean, and standard deviation of blood acetyl fentanyl concentrations for these 41 cases were 0.13–2100 ng/mL, 11 ng/mL, 169.3 ng/mL, and 405.3 ng/mL, respectively. Thirty‐six individuals (88%) had a confirmed history of substance abuse, and all but one case (96%) were ruled multiple drug toxicities. This report characterizes this localized trend of overdose deaths associated with acetyl fentanyl and provides further evidence supporting an alarmingly concentrated opiate and opioid epidemic of both traditional and novel drugs within this region of the United States.     

Simultaneous Determination of 13 Anticoagulant Rodenticidesin Human Blood by Liquid Chromatography–Tandem Mass Spectrometry and its Application in Three Poisoning Cases

Anticoagulant rodenticides are widely used for rodent control around the world. A rapid and sensitive method was developed and validated for the simultaneous determination of 13 anticoagulant rodenticides (coumafuryl, pindone, valone, warfarin, coumatetralyl, coumachlor, diphacinone, dicumarol, chlorophacinone, bromadiolone, difenacoum, flocoumafen, and brodifacoum) in human blood by liquid chromatography–tandem mass spectrometry. After liquid–liquid extraction, the anticoagulant rodenticides were separated on an Eclipse Plus C18 column. Linearities were observed for each analyte in blood ranging from 0.5 to 50 ng/mL, with correlation coefficients over 0.99. The limits of detection ranged from 0.01 to 0.2 ng/mL, and the limits of quantification were 0.5 ng/mL for all analytes. The intraday and interday precisions were <15%, and accuracies ranged from 80.3% to 111.0%. This validated method with high sensitivity has been applied in three anticoagulant rodenticide poisoning cases and has been used successfully in monitoring blood concentrations for months.     

Acetyl Fentanyl: Trends and Concentrations in Metro Detroit

Acetyl fentanyl (N‐[1‐phenethylpiperidin‐4‐yl]‐N‐phenylacetamide) is a potent opioid analgesic with no medicinal uses. We report deaths between 2016 and 2017 at the Medical Examiner's Office in Detroit, MI where acetyl fentanyl was found in the decedent's blood and compare them to previously published deaths between 2015 and 2016. The recent cases (cohort B) had a mean acetyl fentanyl concentration of 0.9 ng/mL (range: 0.1–5.3 ng/mL) and an associated higher concentration of fentanyl along with multiple other drugs present. The older cases (cohort A) had higher concentrations of acetyl fentanyl (mean: 8.9 ng/mL; range: 0.28–37 ng/mL) with lower, yet still toxic, concentrations of fentanyl. We conclude that the cause of death in these recent cases was likely multiple drug toxicity with fentanyl and that the consistently observed lower peripheral blood concentrations of acetyl fentanyl are most likely an artifact in the manufacture of the consumed illicit fentanyl.     

Distribution profile of 2,5-dimethoxy-4-bromoamphetamine (DOB) in rats after oral and subcutaneous doses

2,5-Dimethoxy-4-bromoamphetamine (DOB) is one of the potent hallucinogenic phenylalkylamines, whose ingestion has already caused several deaths reported all over the world. However, there is unsufficient information on DOB properties based on controlled pharmacokinetic studies available. The aim of this study was to clarify the distribution profile of DOB and its phenolic metabolite 2-methoxy-5-hydroxy-4-bromoamphetamine (2M5H4BA) in blood and biological tissues of experimental rats. The rats were administered a 20 mg/kg dose of DOB·HCl by oral ingestion or subcutaneous injection. Plasma and brain, liver and lung tissues were collected at 0.5, 1, 2, 4, 8, 16, and 32 h after dosing (three animals per time point). The samples were prepared by a liquid–liquid extraction procedure and the extracts were assayed by GC–MS. After per oral application, DOB peak plasma level of 320 ng/mL was reached after one-hour post dosing as well as 2M5H4BA peak concentration of 203 ng/mL. A rapid phase of DOB absorption, 2M5H4BA formation and their tissue distribution during the first two hours after application were followed by a slow decrease rate of the elimination process until 32 h. After subcutaneous application, high plasma levels of the unchanged parent drug and relatively reduced formation of its metabolite 2M5H4BA were observed. DOB maximum plasma concentration of 1143 ng/mL was reached after one-hour post application, whereas its metabolite peak level after 8 h was 213 ng/mL. The concentration profiles of both compounds in plasma after per oral and subcutaneous administration revealed the existence of significant first pass effect after per oral administration that significantly affected DOB bioavailability. DOB tissue concentrations exceeded plasma and the highest values were found in the lungs, where drug accumulation occurred with prolonged retention till 32 h after subcutaneous dose. Although the plasma/tissue transfer was more effective for the lipophilic parent drug than for its hydroxylated metabolite 2M5H4BA, the metabolite tissue levels were significant. The hallucinogenic potential of 2M5H4BA appearing in brain remains unclear as nothing is known about its pharmacological activity at present.     

Concurrent detection of heroin, fentanyl, and xylazine in seven drug-related deaths reported from the Philadelphia Medical Examiner's Office

Recreational drugs, such as cocaine and heroin, are often adulterated with other pharmacological agents to either enhance or diminish the drug effects. Between April 21, 2006 and August 8, 2006, the Philadelphia Medical Examiner's Office detected xylazine (a veterinary sedative) and fentanyl (a synthetic opioid) in specimens taken from seven cases. Initial immunoassay screening was performed on urine and blood for fentanyl, opiate, cocaine, phencyclidine (PCP), and benzodiazepines. All tests reported positive were confirmed by gas chromatography-mass spectrometry. All seven xylazine positive cases tested positive for fentanyl and six cases tested positive for 6-acetylmorphine (a metabolite and definitive marker for heroin). The seventh case was positive for morphine and had a history of heroin abuse. Xylazine was present in urine in all seven cases and blood levels were detected in three cases. The blood concentrations ranged from trace to 130 ng/mL. Fentanyl was present in the blood and urine in each case and blood concentrations ranged from 4.7 to 47 ng/mL. Adulteration of illicit drugs has become an epidemic health concern for drug users. Healthcare professionals need to be aware of this issue, so the patients can be treated in an effective, timely manner.     

An Examination of the Postmortem Redistribution of Fentanyl and Interlaboratory Variability,

Fentanyl is a synthetic opioid agonist used for pain control. Often administered as a transdermal patch, it is an interesting drug for study of postmortem redistribution. We hypothesized that fentanyl concentrations would increase over time after death, as measured in blood drawn on the day prior to autopsy and in blood drawn at the time of autopsy in ten cases where fentanyl patches were identified at the scene. Concentrations were compared, and heart blood to femoral blood ratios were calculated as markers of postmortem redistribution. Fentanyl concentrations measured in peripheral blood drawn the day of autopsy (peripheral blood 2 [PB2]) were higher than those drawn the day prior to autopsy (peripheral blood 1 [PB1]) with a mean ratio (PB2/PB1) of 1.80. The ratio of heart blood concentrations (HB) to femoral blood concentrations drawn at autopsy (PB2) had a mean ratio (HB/PB2) of 1.08. Some cases had blood from the same source analyzed at two different laboratories, and concentrations of fentanyl in those samples showed inter‐ and intralaboratory differences up to 25 ng/mL. Postmortem fentanyl concentrations may be affected by antemortem factors, postmortem redistribution, and laboratory variability. Forensic pathologists must use caution in interpreting fentanyl levels as part of death investigation.     

LC-MS/MS分析人全血中五氟利多

目的建立人体全血中五氟利多浓度的液相色谱-质谱联用法（LC-MS/MS）分析方法。方法全血中五氟利多和利培酮（内标）经正己烷液-液提取后,采用Capcell Pak C18色谱柱（250mm×2.0mm5,μm）进行分离,流动相为乙腈：20mmol/L乙酸胺和0.1%甲酸溶液（75∶25,V/V）,流速为0.2mL/min,然后以MS/MS电喷雾正电离的多反应监测扫描方式（MRM）测定。用于定量分析的离子为m/z 524→109（五氟利多）和m/z 411→191（内标）。结果五氟利多的最低检测限为0.2ng/mL,在0.4～400ng/mL浓度范围内线性良好（r=0.9994）,低、中、高浓度（1ng/mL、10ng/mL、100ng/mL）准确度分别为97%,108%和95%,日内和日间RSD均小于15%。结论该方法简便、快速、灵敏,适用于全血中五氟利多浓度的测定。     

Flualprazolam distribution in postmortem samples

The constant emergence of novel psychoactive substances is troubling to both public health officials and legislators. Additionally, sufficient data collection for each new compound can take months up to years. Flualprazolam, a triazolobenzodiazepine, quickly garnered attention as a sedative drug that likely expresses adverse reactions similarly to alprazolam. This study focuses on the distribution of flualprazolam in multiple common postmortem matrices. Central blood, vitreous humor, liver homogenate, brain homogenate, gastric contents, and urine samples from death investigation cases were quantitated when available. Samples were screened with liquid chromatography quadrupole time-of-flight with limit of detection set at 4 ng/ml and quantitated on liquid chromatography tandem mass spectrometry, with concentration range from 4 to 256 ng/ml. From August 2018 to September 2020, 24 central blood samples were quantitated for flualprazolam. Central bloods of 22 cases had concentrations above the limit of quantitation. The average flualprazolam central blood concentration was 16.3 ng/ml with a median of 9.95 ng/ml (4.24–48.0). Additional analyses for unconjugated flualprazolam were performed on at a total of 15 urine samples ( = 14.4, 4.07–36.1 ng/ml), 23 brain homogenates ( = 23.2, 3.99–69.3 ng/g), 23 liver homogenates ( = 50.7, 13.6–156 ng/g), five vitreous humor samples ( = 7.70, 4.03–12 ng/ml), and 12 gastric contents samples ( = 0.36, 0.02–2.51 mg). The cause of death for 13 of the 24 cases listed flualprazolam as a contributing factor of death.     

Oral abuse of fentanyl patches (Duragesic): seven case reports

In order to increase the understanding regarding the oral abuse and potential toxicity of fentanyl patches seven cases were identified over a 3-year period where fentanyl, either alone or in combination with other factors, contributed to death following the oral abuse of Duragesic patches. The decedents comprised three females and four males with ages ranging from 20 to 51 years. Postmortem blood fentanyl concentrations were determined in all cases and ranged from 7 to 97 ng/mL. Two deaths were classified as a fentanyl overdose, three deaths were classified as a fentanyl and ethanol overdose, one death was considered a mixed drug intoxication and the remaining death was determined to be a combination of fentanyl and medical causes. These cases represent the largest reported series of deaths following the oral administration of transdermal fentanyl patches and provide detailed information on the potential for the abuse of transdermal Duragesic patches via this route. The postmortem blood fentanyl concentrations detected for each of the decedents demonstrate the potentially fatal blood concentrations that can arise after this relatively rare route of administration.     

Investigation of Postmortem Absorption and Redistribution After the Application of a Fentanyl Patch

Fentanyl deaths have increased with availability of transdermal patches. Interpretation of postmortem fentanyl levels may be complicated by postmortem redistribution and absorption of fentanyl from a patch. We applied an unused 100‐μg/h fentanyl patch onto the lower abdomen of a decedent with no premortem fentanyl exposure. Ocular fluid, blood, and urine were collected prior to placement, and the decedent was refrigerated for 23 h. Prior to the autopsy, urine, subcutaneous tissue under the patch, and samples from the same anatomic sites were obtained. We observed no fentanyl in any postpatch placement samples (LOD: 0.1 ng/mL for blood and vitreous fluid, 1.0 ng/mL urine, 2.0 ng/g for tissues). Although we observed no postmortem absorption of fentanyl, this was only a single case; therefore, we recommend that patches be removed after receipt of a cadaver before initiation of an autopsy, with the location of removed patch documented.     

Accidental death from hydromorphone ingestion

Abstract: A 15‐year‐old male orally consumed an unknown but fatal amount of sustained release hydromorphone. He was naïve to opioid use. No other drugs or alcohol were involved. The cause of death was acute aspiration‐related bronchopneumonia, secondary to hydromorphone ingestion; the manner of death was accidental. Hydromorphone and hydromorphone‐3‐glucuronide were quantified in postmortem fluids by tandem liquid chromatography–mass spectrometry. The hydromorphone concentrations in the peripheral blood, urine, and vitreous humor were 57, 4460, and 31 ng/mL, respectively. The hydromorphone‐3‐glucuronide concentrations in the corresponding three fluids were 459, 36,400, and 40 ng/mL. Hydromorphone‐3‐glucuronide accumulation probably did not contribute significantly to the opiate toxicity. The proposed minimum lethal hydromorphone blood concentration in the nontolerant user is in the vicinity of 60 ng/mL.     

Parent and Metabolite Opioid Drug Concentrations in Unintentional Deaths Involving Opioid and Benzodiazepine Combinations,,

Effects of benzodiazepines on postmortem opioid parent and parent/metabolite blood concentration ratios were determined for fentanyl‐, hydrocodone‐, methadone‐, or oxycodone‐related accidental deaths. These opioids are partially metabolized by the CYP3A4 enzyme system, which is also affected by diazepam and alprazolam. Opioid/metabolite combinations examined were as follows: fentanyl/norfentanyl, hydrocodone/dihydrocodeine, methadone/EDDP, and oxycodone/oxymorphone. Parent opioid concentrations were analyzed for 877 deaths. Parent/metabolite concentration ratios were analyzed for 349 deaths, excluding cases with co‐intoxicants present known to interfere with opioid elimination. Alprazolam in combination with diazepam significantly decreased median hydrocodone concentrations by 48% (p = 0.01) compared to hydrocodone alone. The methadone parent/metabolite concentration ratio was reduced by 35% in the presence of diazepam compared to methadone alone (p = 0.03). Benzodiazepines did not statistically significantly affect fentanyl or oxycodone concentrations. Possible factors affecting opioid concentrations and possible toxicity development, including any differential effects on specific opioids, should continue to be explored.